The mechanism of atherosclerotic plaque rupture is not known. Current theories focus on the acute triggers of plaque rupture and myocardial infarction such as increased shear or circumferential stress, rupture of the vasa vasorum and vasospasm. We hypothesize that a critical mechanism causing plaque rupture is fatigue failure, the catastrophic rupture of a material following exposure to high-cycle, low-amplitude repetitive stress. Comparisons between material fatigue and plaque rupture demonstrate that this hypothesis is consistent with known physiologic and epidemiologic data on plaque rupture.